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The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARᴷᴼ-PXRᴷᴼ), double humanized CAR and PXR (CARʰ-PXRʰ), and wild-type C57BL/6 mice. Wild-type and CARʰ-PXRʰ mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CARᴷᴼ-PXRᴷᴼ mouse livers and largely reversible in wild-type and CARʰ-PXRʰ mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARʰ-PXRʰ mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.
As researchers continue to seek the expansion of the material base for additive manufacturing, there is a need to focus attention on the Ni–Cu group of alloys which conventionally has wide industrial applications. In this work, the G-NiCu30Nb casting alloy, a variant of the Monel family of alloys with Nb and high Si content is, for the first time, processed via the laser powder bed fusion process (LPBF). Being novel to the LPBF processes, optimum LPBF parameters were determined, and hardness and tensile tests were performed in as-built conditions and after heat treatment at 1000 °C. Microstructures of the as-cast and the as-built condition were compared. Highly dense samples (99.8% density) were achieved after varying hatch distance (80 µm and 140 µm) with scanning speed (550 mm/s–1500 mm/s). There was no significant difference in microhardness between varied hatch distance print sets. Microhardness of the as-built condition (247 HV0.2) exceeded the as-cast microhardness (179 HV0.2.). Tensile specimens built in vertical (V) and horizontal (H) orientations revealed degrees of anisotropy and were superior to conventionally reported figures. Post heat treatment increased ductility from 20% to 31% (V), as well as from 16% to 25% (H), while ultimate tensile strength (UTS) and yield strength (YS) were considerably reduced.
The quest for life on other planets is closely connected with the search for water in liquid state. Recent discoveries of deep oceans on icy moons like Europa and Enceladus have spurred an intensive discussion about how these waters can be accessed. The challenge of this endeavor lies in the unforeseeable requirements on instrumental characteristics both with respect to the scientific and technical methods. The TRIPLE/nanoAUV initiative is aiming at developing a mission concept for exploring exo-oceans and demonstrating the achievements in an earth-analogue context, exploring the ocean under the ice shield of Antarctica and lakes like Dome-C on the Antarctic continent.